Chronic ethanol consumption is associated with chronic pancreatitis and may predispose to pancreatic cancer. Bile reflux into the pancreatic ducts has also been implicated in the development of these diseases. The Principal Investigator has shown that the pancreatic ducts possess a barrier to the back diffusion of HCO3, which is damaged by bile salts, ethanol, and other agents (e.g., aspirin). This increases the permeability of the ducts and may increase the vulnerability of the pancreas to various carcinogens. The objectives of this research program are: 1) to determine the effects of bile salts, ethanol, and aspirin on pancreatic structure and function; 2) to investigate the mechanisms by which aspirin is secreted in pancreatic juice; and 3) to explore the relevance of these observations to pancreatic cancer. To accomplish these objectives, the following experimental models will be employed: 1) Chronic dogs with gastric and pancreatic fistulas, in which the chronic effects of ethanol and/or aspirin on pancreatic secretion will be studied; 2) an in vitro method of pancreatic duct perfusion in which the factors that govern the transport of bile salts, ethanol, and aspirin across the duct mucosa as well as the effects on mucosal function, will be studied; 3) acute cats, in which pancreatic function will be studied using micropuncture techniques (these animals will have been maintained on ethanol and/or aspirin for several months prior to study); and 4) hamsters in which the effects of chronic administration of aspirin and/or ethanol on the development of pancreatic cancer will be studied.